1. Field of the Invention
The invention is generally related to aerosol formulations which include hydrofluoride propellants and prilocaine base.
2. Background Description
Prilocaine is a local anesthetic drug which has the chemical formula: ##STR1##
Prilocaine is described in British Patent 839,943 (1960 to Astra), and takes the form of crystalline needles having a melting point of 37.degree.-38.degree. C. The hydrochloride salt, having the formula Cl.sub.3 H.sub.21 ClN.sub.2 O, is crystallized from ethanol and isopropyl ether, and is readily soluble in water.
Local anesthetic drugs block nerve impulses by interfering with the opening of voltage gated sodium channels of excitable membranes, such as neuronal cell membranes. When enough channels are blocked, neuronal conduction is terminated within the anesthetized portion of the particular nerve axon. This mechanism of pain relief is quite different from those used by analgesic agents.
The potency of anesthetics in clinical situations depends on both the ability to reach the nerve fibers and their intrinsic blocking activities. Factors such as nerve sheath penetration, vascular absorption, and local tissue binding are all important determinants of functional potency. In addition, volume, pH, and buffering capacity of the injected anesthetic solution are important.
Local anesthetics are traditionally injected into the desired site of action by the use of a needle and syringe. Most formulations of local anesthetics are aqueous solutions of the hydrochloride salt forms of the drug in 0.5-2% weight/volume concentrations. These solutions are designed for injection either diffusely into tissue, around nerves, or into the intrathecal or epidural spaces.
The delivery of local anesthetic agents to skin wounds remains a problem and is largely still achieved by injection of the aqueous local anesthetic around or into the wound. This treatment mechanism can be disadvantageous because the needle itself causes pain on penetration, and, the volume of anesthetic solution can cause stretching at the site, which also causes pain. Furthermore, preservatives such as parabens, ethyl alcohol, cetylpyridinium chloride, benzalkonium chloride, and the like, which may be used in the aqueous solution can cause stinging at the wound site.
A topical formulation of 0.5% tetracaine hydrochloride, epinephrine 1:2000, and 11.8% cocaine hydrocloride, is described in Handbook of Pediatric Emergencies, 1994, Ed. Baldwin, Little, Brown and Company. This formulation is applied by holding a cotton ball soaked in the solution for a period of 10-15 minutes. This treatment scheme and formulation suffers from the slow absorption of the salt form of the local anesthetic which requires that the solution be held in place for long periods of time, the use of cotton balls directly on the wound site, and the requirement of cleaning the wound prior to application of the formulation. In addition, in order to obtain deep blocking, the treatment scheme must be supplemented with injection of a local anesthetic formulation.
Topical anesthesia requires rapid absorption of drug in order to block nerve conduction. Topically applied gels and fluids have not proven successful in many environments. For example, intraurethrally delivered lidocaine gel was shown to be no more effective than plain lubricant jelly during cystoscopy (see, Stein et al., Journal of Urology, Jun. 1994, Vol. 151, pages 1518-1521).
Lidocaine has been delivered in aerosol form to the mucous membranes of the airway using nebulized aqueous preparations of the lidocaine hydrochloride salt and using metered dose inhaler (MDI) formulations with chlorofluorocarbon (CFC) propellants and solubilizing and/or dispersing agents. However, experience has shown that these formulations suffer from large droplet formation which prevents satisfactory inhalable or indirect delivery to the upper airway, including the larynx and trachea. In addition, the requirement of organic solvents and adjuvants in the aerosol formulations limits the concentration of the active medicament, and thus limits the dispensable dose. Moreover, these formulations have not been used topically and would not be successful in topical application because the adjuvants and solvents are themselves irritants which would cause pain when administered to sensitive mucous membranes and wounds.
Chlorofluorocarbon (CFC) propellants have been widely used in aerosol formulations; however, CFC propellants are being phased out under international treaties due to their possible adverse impact on the ozone layer. Hydrofluorocarbon (HFC) propellants have been investigated extensively as substitutes for CFCs. While chemically similar to CFCs, HFCs have some property differences that have made formulating certain products very difficult, and particularly formulating medical and pharmaceutical aerosols wherein the ability to provide a controlled amount of drug and, in some instances, particles or droplets of respirable size (e.g., less than 10.mu.m), is extremely important.